...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>PLoS Genetics >Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially
【24h】

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially

机译：临床上 CACNA1A 等位基因对突触功能和神经变性的影响不同

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Dominant mutations in CACNA1A , encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca~(2+)channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila . We previously generated null and partial loss-of-function alleles of cac , the homolog of CACNA1A in Drosophila . Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function. Author summary Calcium channels control the levels of calcium within cells and are important in human health. Indeed, groups of patients with disorders of balance known as ataxia have been found to have mutations in a calcium channel gene in the human genome called CACNA1A . CACNA1A mutations have also been observed in patients with particular forms of migraine leading to temporary paralysis on one side of the body (hemiplegia). Mutations in CACNA1A are increasingly found in even more severe brain phenotypes in childhood. This research focused on a group of 5 patients with that particularly severe CACNA1A -related disease. One of the patients had a particular genetic misspelling in CACNA1A while the other four had nearby misspellings. We used the fruitfly, Drosophila melanogaster , to generate flies with these same misspellings in a genetic background that lacked the fly version of the calcium channel. Interestingly, by studying these flies we saw differences between the mutation in Patient 1 and the other four patients. These differences suggest one of the mutations produces more neurodegeneration, and indeed we see more degeneration in that patient. The fly studies allowed us to understand the function of the mutations in these patients, and were helpful in guiding treatment decisions.
机译：编码神经元P / Q型电压依赖性Ca〜（2+）通道的α-1A亚基的CACNA1A中的显性突变可引起多种神经学表型。罕见的显着严重的早期发作发展延迟和先天性共济失调的病例可归因于从头CACNA1A错义等位基因，其变异影响该通道的S4跨膜区段，其中一些据报道功能丧失。五名患有严重早期共济失调的个体的外显子组测序在一名具有全球发育延迟和进行性小脑萎缩的女孩中发现了一种新的变异（p.R1673P），并在四名具有整体发育延迟的个体中复发了从头开始的p.R1664Q变异。 ，肌张力低下和眼科异常。鉴于这些表型的严重性，我们探讨了它们在果蝇中的功能影响。我们以前在果蝇中生成了CAC（CACNA1A的同系物）的无效和部分功能丧失的等位基因。在这里，我们创建了带有两个著名的保守点突变的转基因野生型和突变基因组抢救构建体。 p.R1673P突变体未能挽救cac的致死性，在基于突变体克隆的视网膜电图（ERG）中显示了功能增益表型，并根据ERGs和透射电子显微镜在衰老果蝇中进化出了神经变性表型。相比之下，p.R1664Q变体表现出功能丧失并且未能发展出神经变性表型。因此，新的R1673P等位基因可能在果蝇和人类中产生神经变性表型，这可能是由于功能的毒性增加所致。作者摘要钙通道控制细胞内钙的水平，对人体健康至关重要。确实，已经发现患有失调症的平衡失调患者群体在人类基因组中称为CACNA1A的钙通道基因中具有突变。在患有特定形式的偏头痛的患者中也观察到了CACNA1A突变，导致身体一侧暂时性麻痹（偏瘫）。在儿童期甚至更严重的脑表型中，越来越多地发现了CACNA1A中的突变。这项研究的重点是5名患有严重CACNA1A相关疾病的患者。其中一名患者在CACNA1A中具有特定的遗传拼写错误，而其他四名患者附近存在拼写错误。我们使用果蝇果蝇（Drosophila melanogaster）在缺乏钙通道果蝇版本的遗传背景中产生了具有相同拼写错误的果蝇。有趣的是，通过研究这些果蝇，我们看到了患者1和其他四位患者的突变之间的差异。这些差异表明，其中一种突变产生了更多的神经退行性变，实际上我们在该患者中看到了更多的退行性变。飞行研究使我们能够了解这些患者中突变的功能，并有助于指导治疗决策。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号